The term "controlled release multiple units formulation" (Bechgaard Hegermann Nielsen, 1978) indicates a pharmaceutical formulation comprising a multiplicity (typically at least 100) of individual coated (or "microencapsulated") units contained in the formulation in such a form that the individual units will be made available from the formulation upon disintegration of the formulation in the stomach of animals, including humans, who have ingested the formulation. Typically, the multiple units formulation may be a gelatin capsule or a tablet which disintegrates in the stomach to make available a multiplicity of coated units.
Controlled release multiple units formulations aim at a controlled release of active substance in a predetermined pattern to reduce and delay the peak plasma concentration without affecting the extent of drug availability. Due to a lower peak plasma concentration, the frequency of undesirable side-effects may be reduced, and due to the delay in the time it takes to obtain the peak plasma concentration and the prolongation of the time above the therapeutically active plasma concentration, the dosage frequency may be reduced to a dosage taken only twice or once a day, in order to improve patient compliance.
A further advantage of the controlled release multiple units dosage form is that high local concentration of the active substance in the gastrointestinal system is avoided, due to the units being distributed freely throughout the gastrointestinal tract.
Drug release from a controlled release dosage form is generally controlled by a coating outside an active core. The release can be achieved
a) by diffusion: the coating swells in aqueous environment so that the active substance can diffuse through the stagnant liquid phase contained in the coating polymer; or PA1 b) by osmosis: the coating is semipermeable, i.e. only water can penetrate the coating polymer and dissolve the active substance, this will lead to a pressure buildup inside the coating, in order to allow the active to be released from the unit a hole or channel with a well defined area must be formed in the coating, this can be achieved either by laser drilling (SE patent 435 897--U.S. Pat. No. 4,256,108 to Alza) or by incorporation of a substance which will form the channels by erosion after ingestion (U.S. Pat. No. 4,687,660 and European patent application 0 171 457 to Wellcome), should the coating have any weak spots or cracks in it these will increase the release area and as a result give varying dissolution rates for different units, i.e. zero order release will not be achieved for the hole dose, or PA1 c) by erosion: the coating will disintegrate by a process dependent on, e.g. enzymes or pH and leave the active core exposed to rapid dissolution. The importance of a pH independent diffusion with respect to obtaining a reproducible rate of availability and to minimizing intra- and intersubject variations is known (GB patent 1,468,172 and Bechgaard & Baggesen, 1980). It is also known that controlled drug release in vivo can be achieved through an erodable process by enteric coating of a multiple units dosage form (Green, 1966; McDonald et al., 1977; Bogentoft et al., 1978).
The present invention deals with multiple units dosage forms controlled by diffusion membranes. Contrary to previously known diffusion membranes used for multiple unit dosages the membrane according to the invention is non-swellable in water and gastrointestinal fluids. Furthermore, the polymer used must be insoluble in and impermeable to water and pores are formed in the membrane after ingestion by a pH independent erosion process. The pores will give the coating a sponge-like appearance and will be filled with stagnant liquid where the active substance can diffuse out from the core.